Registration Dossier

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Remarks:
No further cohorts can be identified at this time as there is no existing data on this substance for the 90-day or development endpoints.
Type of information:
experimental study planned (based on read-across)
Study period:
Subject to decision on testing proposal
Justification for type of information:
A read-across approach is applied between Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3) for the human health endpoints due to the structural similarity of the two reaction products (Scenario 6 in ECHA’s RAAF document), both resulting from the same starting materials (only the ratio is different), and through the same manufacturing process.
Commercial MEA Polyborate products are commonly formulated at either 1:1 or 1:3 mole ratios of MEA to boric acid, or sometimes at ratios in between. All compositions in this range contain equilibrium mixtures of the exact same chemical species, but with somewhat different population distributions.
The existing physico-chemical, toxicological, environmental fate and ecotoxicological data already showed good correlation with no significant differences between the two ratios.
The results of the newly commissioned, additional anchoring studies (water solubility, vapour pressure and octanol-water coefficient, Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assays, acute toxicity studies via dermal route and oral route) showed good correlation between Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3), and therefore further supported our category hypothesis.

However, no toxicokinetic (absorption, metabolism, distribution, elimination) data is available for MEA-Polyborate. Available data is primarily physico-chemical properties that influence the absorption and distribution of the substance in the body. This data provides limited information indicating a read-across approach between the reaction products of MEA Polyborate 1:1 and 1:3 for the human health endpoints is likely justified for repeated dose studies including developmental toxicity studies. However, since no data is available on the metabolism of MEA-Polyborate, additional data is needed to justify read across for repeated dose studies. In this case data from dose range finding studies for the proposed developmental toxicity and 90-day toxicity studies will provide the requisite information if read-across is justified.

Category: MEA Polyborates

TESTING PROPOSAL ON VERTEBRATE ANIMALS
Extended one-generation reproductive toxicity study (EOGRTS, Annex X, Section 8.7.3.; Test method: EU B.56, OECD TG 443) in rats or rabbits, oral route

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out
: Reaction products of monoethanolamine and boric acid (1:3)
- Name of the substance for which the testing proposal will be used [if different from tested substance]
: Reaction products of monoethanolamine and boric acid (1:1)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies and non-GLP studies :
There is no existing reliable (GLP or non-GLP) data on the reproductive toxicity in rats.
This is a standard information requirement for which data must be provided. The information on this endpoint is not available for the registered substance, but needs to be present in the registration dossier to meet the information requirements.

- Historical human data: A literature search and SIEF survey has not identified historical data on human exposure to Reaction products of monoethanolamine and boric acid 1:1/ 1:3 and its toxicological effects. Adaptation based on historical human data, therefore, is not possible.

- (Q)SAR
Due to the presence of inorganics and the complex chemistry, the substance falls outside of the applicability domain of the globally recognized (Q)SAR models. Therefore, no (Q)SAR modelling has been carried out on Reaction products of monoethanolamine and boric acid (1:1) / Reaction products of monoethanolamine and boric acid (1:3)

- In vitro methods
The application of in vitro methods is not relevant to the assessment of the effects of MEA Polyborates 1:1/1:3 in an extended one-generation reproductive toxicity study in rats (via the oral route) given the biological complexity of the endpoint.

- Weight of evidence: Upon reviewing all available information, including GLP and non-GLP studies, in vitro and QSAR methods, and based on our category approach, a tiered testing approach is proposed. A weight of evidence based adaptation, however, is not considered to be applicable.

- Substance-tailored exposure driven testing: Considering the intended uses of the substance, exposure-driven adaptation is not applicable.

- Grouping and read-across
It is proposed that the Expended One-Generation Reproductive Toxicity Study (EOGRTS, OECD 443) to be conducted in MEA Polyborate 1:3. The result will be used to fill the reproductive toxicty information requirements of MEA Polyborate 1:1.
Category name: MEA Polyborates

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Section 8.7.3 of Annex IX of REACH (Extended OneGeneration Reproductive Toxicity Study (B.56 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 443),) states that “An Extended One-Generation Reproductive Toxicity Study with the extension of cohort 1B to include the F2 generation shall be proposed by the registrant.

Testing of the Extended OneGeneration Reproductive Toxicity of rats (via the oral route) on MEA Polyborates 1:3 will address the requirement of Section 8.7.3 of Annex IX of REACH.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed
It is proposed that an Extended one-generation reproductive toxicity study (EOGRTS, Annex X, Section 8.7.3.; Test method: EU B.56, OECD TG 443) in rats or rabbits, oral route will be conducted on MEA Polyborates 1:3 according to OECD Guideline for testing of chemicals 443.
Further reproductive and developmental studies may potentially be proposed based on the result of developmental studies (OECD TG414) and the EOGRTS study proposed on MEA Polyborates 1:3.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Justification for study design:
No further cohorts can be identified at this time as there is no existing data on this substance for the 90-day or development endpoints.

Test material

Reference
Name:
Unnamed
Test material form:
liquid
Remarks:
clear colourless
Details on test material:
UVCB
At room temperature protected from light
31 March 2018 (expiry date)

Test animals

Species:
rat

Administration / exposure

Details on exposure:
Oral administration of the test item is relevant because physicochemical properties mean systemic uptake via the oral route is more likely than via the dermal or inhalation routes.
Details on study design:
The basic protocol design of the OECD 443 (cohorts 1A and 1B, without extension to the second generation) will be performed. In addition, the ECHA specific modifications of the OECD 443 will be incorporated into the protocol design so that the premating dosing period will be for 10 weeks and the dose levels will be set according to general toxicity.

Physicochemical properties mean that category substances are predicted to be absorbed very slowly via the dermal route and no significant uptake is expected. With respect to the inhalation route, the substances have a vapour pressure of < 0.01 Pa at 25 °C and, under normal conditions of handling and use, absorption of test material in the form of vapours, gases or mists via the respiratory tract is not expected to be relevant or significant.

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion